Nature Study Reveals Novel Immune Mechanism Against Pathogenic Bacteria with Therapeutic Implications

Group A Streptococcus (GAS), also known as Streptococcus pyogenes, is a highly virulent pathogen that is widely present in nature. It can cause various diseases through infections of the host's skin and respiratory mucosa, including scarlet fever, erysipelas, fatal necrotizing fasciitis, toxic shock syndrome, and sepsis [1, 2]. Among these, septic shock is one of the main clinical symptoms in patients with severe COVID-19 pneumonia. According to the World Health Organization, approximately 700 million people worldwide are infected annually, with more than 500,000 deaths resulting from diseases caused by these infections [6], and about 30% of patients die from invasive severe infections.

GAS Morphology under Electron Microscope

Source of the image: Institute of Infectious Diseases, Chinese Center for Disease Control and Prevention

The infectivity and invasiveness of Group A Streptococcus (GAS) are closely related to its secreted virulence factors, such as streptococcal pyrogenic exotoxin B (SpeB) [3], but the specific molecular mechanism remains unknown. On February 2, 2022, Dr. Youdong Pan, Chief Scientific Officer of NeoCura, was a co-first author of a research paper published in Nature titled “Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.” This study first discovered and reported that the GAS virulence factor SpeB cuts and activates the GSDMA molecule, triggering pyroptosis in skin epithelial cells to inhibit systemic infection.

Researchers first utilized a Streptococcus pyogenes skin infection model and found that, compared to the wild-type strain, the infection sites in mice exhibited severe purulent and necrotic lesions. In contrast, no significant skin ulceration was observed in mice infected with the SpeB-deficient strain, with a marked reduction in immune cell infiltration at the infection site. Meanwhile, the mice showed more severe systemic infection and mortality. Furthermore, using a primary epithelial cell infection model, researchers discovered that the absence of SpeB caused Streptococcus pyogenes to lose its ability to induce pyroptosis. Building on this, through a CRISPR/Cas9 whole-genome knockout screening platform, the key effector protein responsible for SpeB-induced pyroptosis was identified: GSDMA [4, 5]. Finally, a detailed analysis was conducted on the molecular mechanism and in vivo function of how SpeB cleaves/activates GSDMA and regulates Streptococcus pyogenes infection and invasion.

In summary, this study is the first to discover and report that the GSDMA molecule expressed in skin epithelial cells acts as both an exogenous pathogen receptor to recognize the virulence factor SpeB of Streptococcus pyogenes and as an immune effector inducing pyroptosis and suppurative necrotic skin lesions, thereby controlling further systemic infection by the pathogen. The study reveals a novel mechanism in the body's immune defense response: a single protein (GSDMA) functioning as both a pathogen receptor and a host effector. It also provides new targets and insights for the clinical treatment of related diseases caused by pathogenic infections such as Streptococcus pyogenes. (Bioon)

References

1.Aziz, R.K. and M. Kotb, Rise and persistence of global M1T1 clone of Streptococcus pyogenes. Emerg Infect Dis, 2008. 14(10): p. 1511-7.

2.Cleary, P.P., et al., Clonal basis for resurgence of serious Streptococcus pyogenes disease in the 1980s. Lancet, 1992. 339(8792): p. 518-21.

3.Sumby, P., et al., Evolutionary origin and emergence of a highly successful clone of serotype M1 group a Streptococcus involved multiple horizontal gene transfer events. J Infect Dis, 2005. 192(5): p. 771-82.

4.Broz, P., P. Pelegrin, and F. Shao, The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol, 2020. 20(3): p. 143-157.

5.Liu, X., et al., Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov, 2021. 20(5): p. 384-405.

6.Sanyahumbi AS, Colquhoun S, et al. Streptococcus pyogenes Basic Biology to Clinical Manifestations. Oklahoma City, OK, USA: University of Oklahoma Health Sciences Center; 2016. p. 661- 704.